Dichloromethane → 4-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

HRID 729619Notes

Reaction equation

HRID 729619 reaction equation
ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)[CH:11]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([NH2:50])=[CH:42][N:41]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.ClCCl>CS(C)=O.O>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH2:35][CH:36]([O:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([NH:50][C:5]([NH:6][C:7]3[N:8]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[N:9]=[C:10]([C:12]4([CH3:15])[CH2:13][CH2:14]4)[CH:11]=3)=[O:4])=[CH:42][N:41]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 81531DiisopropylethylamineHCID 57832815[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloroethyl esterHCID 578328234-(4-Amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 690528384-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl esterYield 59.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

Dissolve [5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 3.20 g, 7.94 mmol and 2.0 equiv) and 4-(4-amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 22, 1.37 g, 3.97 mmol, 1.0 equiv) in 7 mL of anhydrous DMSO, add diisopropylethyl amine (DIPEA, 1.36 mL, 7.94 mmol, 2.0 equiv) and heat in a sealed tube with stirring for 20 hours at 80° C. Pour the solution in a 1:1 v/v mixture of dichloromethane and iced water. Extract the aqueous phase with dichloromethane (2×50 mL), and wash the combined organic layers with water (2×50 mL) and aqueous sodium chloride (100 mL). Dry the organic solution over sodium sulfate and evaporate under reduced pressure. Subject residue to silica gel chromatography eluting with a gradient from 15% to 80% EtOAc in hexanes to afford 1.40 g of 4-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a pure foamy cream solid. 59% yield. ES+ (m/z) 597.4 [M+H].

Workup

  1. temperatureheat in a sealed tube
  2. additionPour the solution
  3. extractionExtract the aqueous phase with dichloromethane (2×50 mL)
  4. washwash the combined organic layers with water (2×50 mL) and aqueous sodium chloride (100 mL)
  5. dry with materialDry the organic solution over sodium sulfate
  6. customevaporate under reduced pressure
  7. washSubject residue to silica gel chromatography eluting with a gradient from 15% to 80% EtOAc in hexanes

Sources & evidence

ORD record
ord-6cfd848b4b7649b68b351f345bb1318d
Source dataset
uspto-grants-2009_09
Patent number
US07582638B2

Reaction notes

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